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description Sirolimus derivatives Afinitor - Novartis Mechanism of action Mammalian target of rapamycin Treatment of advanced kidney cancer everolimus approved indications side effects

CAS No.159351-69-6
Chemical Name:Everolimus
Synonyms:SDZRAD;RAD-001;Certica;Afinitor;Certican;Zortress;Everolimus;CERTICAN(R);EveroliMus API;Everolimus, >=98%
Molecular Formula:C53H83NO14
Formula Weight:958.232
MOL File:159351-69-6.mol
Everolimus Property
Melting point : NA
storage temp. : −20°C
Water Solubility : Soluble in dimethysulfoxide,ethanol and chloroform. Slightly soluble in water.
Stability:: Hygroscopic
Hazard Codes : T,Xn,F
Risk Statements : 48/25-36-20/21/22-11
Safety Statements : 45-36/37-26-16
WGK Germany : 2
F : 10

Everolimus Chemical Properties,Usage,Production

Everolimus is a Kinase Inhibitor. It’s brand name is Afinitor. Everolimus is a derivative of the natural macrocyclic lactone sirolimus with immunosuppressant and anti-angiogenic properties.The mechanism of action of everolimus is as a Protein Kinase Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor, and Cytochrome P450 2D6 Inhibitor.
In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production.
Everolimus is a biological therapy treatment for
Advanced breast cancer if you have been through the menopause (post menopausal). You take it with the hormone therapy drug exemestane
Advanced kidney cancer that has come back either during or after treatment.
Neuroendocrine tumours of the pancreas that can't be removed with surgery or have spread (metastatic disease).
Researchers are also looking at everolimus as a treatment for head and neck cancer and cancer of the food pipe (oesophageal cancer).
Sirolimus derivatives
Everolimus is sirolimus derivatives. It is also known as 40-O-(2-hydroxyethyl)-rapamycin, or 40-O-(2-hydroxyethyl)-sirolimus, and it is belong to kinase drugs which interfere with cell communication and prevent tumor cell growth. It is a kind of oral mammals of rapamycin (mTOR) inhibitors, and is mainly used to prevent clinical renal transplantation and rejection after heart transplant surgery. Now it can also be used in the treatment in patients with advanced kidney cancer who has used two kinds of inhibition of vascular endothelial growth factor receptor kinase inhibitors: chougny for sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, bayer) and has less side effects.
Sunitinib and sorafenib are kinase inhibitor (role in a variety of targeted cells), and everolimus blocks the target of rapamycin (mTOR) specific proteins of mammals, which disturb cancer cell growth, differentiation and metabolism. The mTOR dysregulation in some tumors. Everolimus combined with intracellular protein FKBP-12 to generate inhibition of complex, thus inhibits mTOR kinase activity, and reduces the mTOR downstream effector S6 ribosomal protein kinase (S6K1) and eukaryotic extension factor 4 e binding protein (4 e-BP) activity at the same time. In addition everolimus inhibits expression of hypoxia-inducible factor (HIF-1) and reduces the expression of vascular endothelial growth factor (VEGF). Studies have shown that it can decrease the in vivo and in vitro cell proliferation, angiogenesis, and glucose uptake.
1, mTOR is a serine, threonine kinase, P13K/AKT downstream products.
2, sirolimus is also called rapamycin.
Afinitor - Novartis
On February 26, 2016, the U. S. Food and Drug Administration approved everolimus (Afinitor , Novartis) for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
Today’s approval was based on demonstration of improvement in progression-free survival (PFS) in a multicenter, randomized (2:1), placebo-controlled trial of everolimus 10 mg orally once daily plus best supportive care (BSC) to placebo plus BSC.
The clinical trial enrolled 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), neuroendocrine tumors (NET) of gastrointestinal or lung origin. All patients were required to have evidence of disease progression within 6 months prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) based on independent radiological assessment per RECIST. Median PFS were 11 months and 3.9 months in the everolimus and placebo arms, respectively [HR 0.48 (95% CI: 0.35, 0.67), p <0.001, stratified log rank test]. Overall response rates were 2% in the everolimus arm and 1% in the placebo arm. At the planned interim analysis, there was no statistically significant difference in overall survival between arms.
Safety data were evaluated in 300 patients who received at least one dose of investigational drug. The median exposure duration to everolimus was 9.3 months; 64% of patients were treated for greater than or equal to 6 months and 39% were treated for greater than or equal to12 months.
Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.
The recommended dose and schedule for everolimus is 10 mg orally once daily.
Mechanism of action
Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake.
Mammalian target of rapamycin
The activation of rapamycin target molecule (mTOR) will promote the proliferation and survival of cancer cells, at the same time it can also cause blood vessels origin way signaling in endothelial cells. Rapamycin combined with intracellular protein to produce FK506-binding protein 12 (FKBP12), the resulting protein drug compounds can inhibit mTOR kinase activity. Rapamycin has the effect of immunosuppression, antifungal, antiviral, antitumor activity, blood vessels protection function, but its main application is its immune inhibition, and was approved by the FDA for anti-rejection treatment in organ transplantation in 1999. Many rapamycin derivatives have been synthesized mainly to improve the drug characteristics, these efforts also resulted in the vein for treatment of renal cancer carry rui Selma (temsirolimus) and oral use according to the dimension of therapy (everolimus) discovery and research. Everolimus has been approved for the treatment of rejection after organ transplantation by Europe in 2003, and was subject to market in the name of Certica.
The above information is edited by the Chemicalbook Duan Yalan.
Treatment of advanced kidney cancer
Kidney cancer accounts for 2-3% of cancer, early kidney cancer is priority to surgery, the late is given priority to with chemotherapy, and are often poor response to chemotherapy and radiotherapy. In fact, the usage of interleukin 2 alone or combined alpha interferon on immune therapy are limited in clinical due to its toxicity and the generally poor response to treatment.
Renal cell carcinoma is the most common type of kidney cancer, disease in renal tubular epithelial cells. Usually, this kind of cancer cells in patients can produce resistance to radiotherapy and chemotherapy in standard treatment, such as to make the most of the people through the treatment of kidney remove. If patients with cancerous parts only limit in the kidney, 60-70% of the patients will survive for five years, but if the cancer cells transfer, the life patients survival will be greatly reduced. On March 30, 2009, Novartis original immunosuppressive drug everolimus(everolimus, Afinitor) used for kidney obtained FDA approval. The results showed that, everolimus can obviously increase progression-free survival of cancer patients. It provides a new treatment option for advanced renal cell cancer patients of no avail to Sunitinib or Sorafenib.
In August 2009, the European commission has approved Novartis production of Afinitor (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC), the European society of medical oncology, Europe urinary tumor urogenital group (EAU), Spain (SOGUG), the European organization for research and treatment of cancer (EORTC), the European medical oncology (ESMO) treatment guidelines and British consensus guidelines and several European authority guidelines updated, recommend Afinitor as second-line treatment in patients with advanced kidney cancer drugs.
everolimus approved indications
Everolimus is approved to treat:
Breast cancer. It is used in combination with exemestane in postmenopausal women with advanced hormone receptor positive (HR+) breast cancer that is also HER2 negative (HER2-) and has not gotten better with other chemotherapy.
Pancreatic cancer, gastrointestinal cancer, and lung cancer (certain types). It is used in adults with progressive neuroendocrine tumors that cannot be removed by surgery, are locally advanced, or have metastasized (spread to other parts of the body).
Renal cell carcinoma (a type of kidney cancer) that is advanced, in adults who have not gotten better with other chemotherapy.
Subependymal giant cell astrocytoma in adults and children who have tuberous sclerosis and are not able to have surgery. Everolimus is available as tablets (Afinitor) or tablets for oral suspension (Afinitor Disperz). Only Afinitor Disperz is used in children.
The use of everolimus to treat cancer is approved for the Afinitor brand. Everolimus is also approved to treat transplant rejection. This use is approved for the Zortress brand.
Everolimus is also being studied in the treatment of other types of cancer.
side effects
Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening.

Stop using Everolimus (Afinitor) and call your doctor at once if you have:

  • new or worsening cough, chest pain, wheezing, feeling short of breath;
  • signs of infection--fever, chills, joint pain, red or swollen gums, painful mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling light-headed;
  • kidney problems--little or no urination; painful or difficult urination; swelling in your feet or ankles; feeling tired or short of breath;
  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • any wound that will not heal; or
  • a surgical incision that is red, warm, swollen, painful, bleeding, or oozing pus.

Common side effects may include:
  • infections, cough, nosebleeds;
  • mouth sores, taste problems, dry mouth;
  • nausea, vomiting, diarrhea, constipation;
  • weight loss, feeling weak or tired;
  • pain or swelling anywhere in your body;
  • dry skin, rash, acne;
  • missed menstrual periods;
  • unusual changes in mood or behavior;
  • sleep problems (insomnia);
  • dizziness, headache; or
  • high blood sugar--increased thirst or urination, hunger, fruity breath odor, blurred vision.
Chemical Properties
Off White Solid
Macrolide immunosuppressant; derivative of Rapamycin. Inhibits cytokine-mediated lymphocyte proliferation
Everolimus (RAD001) is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM
Everolimus Macrolide immunosuppressant; Everolimus is a derivative of Rapamycin. Everolimus inhibits cytokine-mediated lymphocyte proliferation.
Everolimus is a semi-synthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group with a silyl-protected hydroxyethyl triflate moiety, followed by addition of an ethylhydroxy moiety to provide greater stability and bioavailability. Like all tacrolimus analogues, everolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing it from interacting with target proteins. Everolimus is extensively cited in the literature with over 2,000 citations.
ChEBI: A macrocyclic lactone that is rapamycin in which the hydroxy group attached to the cyclohexyl moiety has been converted to the corresponding 2-hydroxyethyl ether. It is an immunosuppressant and antineoplastic agent.
Everolimus Preparation Products And Raw materials
Raw materials
Preparation Products
Everolimus Suppliers      Global( 178)Suppliers     
Dalian Meilun Biotech Co., Ltd. 0411-66771943;0411-667719420411-66771945sales@meilune.comChina 4853 58
EASON Chemical Co., LIMITED 15157289797 135668786890576-88860891info@seasonsbio.comChina 54 58
Suzhou Unite pharmTech Co., Ltd , +86-013222993784 +86-512-82177310+86-512-82177310 +86-512-62575043sales@unite-pharm.comChina 100 56
Hunan Cangood Medical Technology Ltd. 400-026-9899, +86-731-83862081, +86-18974920699+86-731-86905278info@cangood.cnChina 72 50
Taizhou KEDE Chemical Co., Ltd 0576-84613060 13093829633 138576312860576-84613060sales@kedechemical.comChina 291 60
MedChemexpress LLC 609-228-6898609-228-5909sales@medchemexpress.comUnited States 4801 58
Shanghai Linka Biotechnology Co., Ltd. 15901858719 QQ2126935757021-61155234sales@linkachem.comChina 283 55
BrightGene Bio-medical Technology Co., Ltd. +86 (512) 62551767+86 (512) 62551799richardchan@bright-gene.comChina 38 70
Wuhan Biocar Bio-Pharm Co., Ltd. 1776400375386-027-87050469sales@biocar.cnChina 1293 50
Shanghai Boyle Chemical Co., Ltd. 86-21-5018059686-21-57758967sales@boylechem.comChina 2770 55
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159351-69-6 42-O-(2-Hydroxyethyl)-rapamycin Certica RAD-001 SDZRAD Rapamycin, 42-O-(2-hydroxyethyl)- Everolimus C53H83NO14 Certican All Inhibitors Inhibitors Intermediates & Fine Chemicals Pharmaceuticals CERTICAN(R) EveroliMus(RAD-001) (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24Z,26Z,28Z,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-Methoxycyclohexyl]propan-2-yl]-19,30-diMethoxy-15,17,21,23,29,35-hexaMethyl-11,36-dioxa-4-azatricyclo[^{4,9}]hexatriaconta-16,2 Afinitor Zortress Inhibitor Antineoplastic protein kinase inhibitors mTOR inhibitor EveroliMus API Certican, Zortress, Afinitor Anti-cancer&immunity PI3K/Akt/mTOR 23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine, rapamycin deriv Everolimus solution Everolimus, >=98%
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